Oral Antithrombotic Therapy After Acute Coronary Syndromes

EDITORIAL Euro Intervention Oral antithrombotic therapy after acute coronary syndromes:

2017;13: “dual antiplatelet” or “dual pathway”? 773-775

Davide Capodanno, MD, PhD, Deputy Editor

There is something going on in the field of long-term antithrom- production of thromboxane A2. The other part of the problem is botic therapy for patients with a recent acute coronary syndrome fibrin. Polymerised fibrin contributes together with platelets to (ACS), where twelve months of dual antiplatelet therapy (DAPT) thrombus formation, which calls the coagulation cascade into with low-dose aspirin and a potent P2Y12 inhibitor is regarded as question. In a modern view, platelets and coagulation factors are the standard of care1. The superiority of prasugrel and ticagrelor no longer discerned as separate players in the pathophysiological over the earlier-generation clopidogrel is undisputed, but some mechanism that leads to ACS, and their interplay is emphasised problems remain2. For example, in TRITON and PLATO, the (Figure 1). Where the link between the two pathways becomes residual rates of ischaemic events were still as high as 9.9% at apparent is especially at the level of thrombin, which is not only 15 months with prasugrel and 9.8% at 12 months with ticagrelor3,4. the activated coagulation factor that converts fibrinogen into In addition, both drugs increased the rate of major bleeding unre- fibrin, but also a potent platelet activator itself through the PAR-1 lated to coronary artery bypass grafting as compared with clopi- and PAR-4 receptors. dogrel. In aggregate, these findings underscore that, even in the Can we use approved drugs to reduce thrombin-mediated plate- era of potent P2Y12 inhibitors, there is room for improvement with let activation, and hit the sweet spot of improved efficacy and respect to both efficacy and safety. acceptable safety? One attempt was using vorapaxar, a blocker When we target platelets to reduce thrombus formation, we of the PAR-1 receptor, but this strategy proved ineffective and tackle only one part of the problem (Figure 1). Aspirin inhibits harmful in the large (N=12,944) TRACER trial5. Another chance the cyclooxygenase 1, thus restraining the production of throm- is decreasing the generation of thrombin, or blocking thromboxane A2, a stimulator of platelet activation and aggregation. bin directly, by means of oral anticoagulants. Indeed, the idea Prasugrel, ticagrelor and clopidogrel block the platelet recep- of using oral anticoagulants in ACS patients is not that new. In tor for adenosine diphosphate, another potent agonist promot- 2006, a meta-analysis of 7,836 ACS patients from 10 studies ing activation and aggregation, and also modulate indirectly the suggested that adding warfarin with an international normalised ratio 2-3 to aspirin decreases the composite of death, myocardial infarction and stroke by 28% at the price of a 2.3-fold increased 6 Plaque disruption risk of bleeding . Non-vitamin K antagonist oral anticoagulants Vit. K (NOACs) are valuable alternatives to warfarin, with a favour- Warfarin Tissue factor/VIIa Collagen vWF Acenocumarol able safety profile demonstrated in settings such as venous throm- Coagulation cascade Platelet adhesion and secretion boembolism and atrial fibrillation. ESTEEM, a phase 2 trial of Rivaroxaban Aspirin COX-1ADP Ticlopidine Apixaban Factor Xa Clopidogrel the direct thrombin inhibitor ximelagatran, showed promise in Edoxaban TXA Prasugrel 2 Ticagrelor ACS, with no increase in bleeding and a significant reduction in Prothrombin (II) ischaemic events7. Ximelagatran, however, has been withdrawn Dabigatran Thrombin (IIa) PAR 1/4 Platelet activation/aggregation pending applications for marketing approval (and its distribution Vorapaxar GP IIb/IIIa activation discontinued in countries where the drug had been approved) after D OI: OI: Fibrinogen Fibrin Platelet aggregation reports of hepatotoxicity. Three more phase 2 trials of dabigatran 10.4244/EIJV13I7A112 Thrombus (RE-DEEM), another thrombin inhibitor, and the factor X inhibitors darexaban (RUBY-1) and letaxaban (AXOM-ACS) failed to Figure 1. Schematic representation of factors involved in thrombus suggest any meaningful ischaemic benefit, and were associated 8-10 formation and targets of oral antithrombotic drugs. ADP: adenosine with a dose-dependent increase in bleeding . diphosphate; COX-1: cyclooxygenase 1; PAR 1/4: platelet-activated The only NOACs whose clinical development progressed to receptors 1 and 4; TXA2: thromboxane A2; Vit. K: vitamin K; a phase 3 ACS trial – following satisfactory results in phase 2 vWF: von Willebrand Factor investigations – are apixaban and rivaroxaban11. In the phase 2

© Europa Digital & Publishing 2017. All rights reserved. 773 Euro Intervention APPRAISE-1 trial, apixaban was investigated at escalating doses investigation. NOACs decrease bleeding compared with warfa- in 1,715 patients with recent ACS12. The 2.5 mg twice daily dose rin in patients with atrial fibrillation, but this might not be true was selected for testing in the subsequent and larger (N=7,392) when these drugs are added on top of DAPT in patients with

2017;13: APPRAISE-2 study, where nevertheless no evidence of efficacy ACS. Removing aspirin from the drug cocktail, not necessarily was demonstrated, and bleeding increased by 2.6-fold compared in the acute phase, is an option to decrease bleeding, but whether with placebo13. Rivaroxaban was first tested in 3,491 ACS patients this strategy is also effective was not addressed by the relatively 773-775 from the phase 2 ATLAS-ACS trial14. Two low doses, 2.5 mg small GEMINI-ACS 1, and its net clinical benefit remains uncer- twice daily and 5 mg twice daily, were selected for phase 3 testing tain. Also unclear is whether strategies modulating the intensity due to their potential of reducing ischaemic events in both patients of DAPT (i.e., de-escalation from prasugrel or ticagrelor to clopi- on aspirin alone and those on DAPT with aspirin and clopidogrel, dogrel after the acute phase) confer the same vascular protection and despite some nominal increase in bleeding compared with on top of the expected decrease in bleeding complications18,19. If placebo14. In ATLAS-ACS 2 (N=15,526), both doses of rivar- proven so, one might also envisage future scenarios where the oxaban reduced the primary ischaemic endpoint, but the 2.5 mg acute phase of ACS will be treated with more potent antiplatelet twice daily dose also reduced cardiovascular and overall mortality, therapy (i.e., DAPT with ticagrelor or prasugrel) and the chronic a survival benefit that was missed by the 5 mg twice daily dose15. phase with less antiplatelet intensity (i.e., the 60 mg or 90 mg These results – along with a more favourable safety profile – led twice daily dose of ticagrelor alone, or DAPT with aspirin and to the regulatory approval of the rivaroxaban 2.5 mg twice daily clopidogrel) combined with a “touch” of antithrombin effect (i.e., dose for ACS, and a IIb recommendation in clinical guidelines. the low dose of rivaroxaban). Recently, among patients with sta- This cautious recommendation reflects the significant increase ble atherosclerotic vascular disease, a strategy of aspirin plus low in major and intracranial (albeit non-fatal) bleeding observed in dose rivaroxaban showed better cardiovascular outcomes than the ATLAS-ACS 2, even with the lower dose of rivaroxaban. use of aspirin alone20. Head-to-head outcome trials of “dual anti- Thus, cardiologists are confronted with different potential strate- platelet” versus “dual-pathway” strategies are of utmost interest gies for long-term antithrombotic therapy management of patients and welcome in ACS. with ACS, and there is a paucity or lack of comparisons to facilitate clinical decisions in daily practice. A recent randomised comparison References of DAPT with prasugrel and ticagrelor in patients with ST-segment 1. Gargiulo G, Valgimigli M, Capodanno D, Bittl JA. State of elevation ACS showed no differences between these regimens, the art: duration of dual antiplatelet therapy after percutaneous but the study conclusions were limited by low statistical power16. coronary intervention and coronary stent implantation – past, pre- Triple therapy with DAPT and the low dose of rivaroxaban has sent and future perspectives. EuroIntervention. 2017;13:717-33. shown the largest reduction in cardiovascular and total mortality so 2. Wijns W. The EAPCI Dual AntiPlatelet Therapy survey: the far reported in post-ACS patients, but the uptake of this strategy is difficult translation of scientific evidence in clinical interventional hampered by multiple considerations, including the modest appeal practice. EuroIntervention. 2015;11:15, 17. of “add-on” antithrombotic strategies in general for both patients 3. Wiviott SD, Braunwald E, McCabe CH, Montalescot G, and physicians, the increased rates of major and intracranial bleed- Ruzyllo W, Gottlieb S, Neumann FJ, Ardissino D, De Servi S, ing shown in ATLAS-ACS 2, and the lack of comparisons versus Murphy SA, Riesmeyer J, Weerakkody G, Gibson CM, Antman EM; modern DAPT with prasugrel or ticagrelor. Simplification of the TRITON-TIMI 38 Investigators. Prasugrel versus clopidogrel in ATLAS-ACS 2 strategy has recently been attempted in GEMINI- patients with acute coronary syndromes. N Engl J Med. 2007;357: ACS 1, a phase 2 investigation of combining low-dose rivaroxaban 2001-15.

with a P2Y12 inhibitor (ticagrelor or clopidogrel) for the treatment 4. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, of patients with stabilised ACS17. This strategy (which essentially Held C, Horrow J, Husted S, James S, Katus H, Mahaffey KW, replaces aspirin with a low dose of rivaroxaban after a short period Scirica BM, Skene A, Steg PG, Storey RF, Harrington RA; PLATO of DAPT) showed similar risks of clinically significant bleeding Investigators, Freij A, Thorsén M. Ticagrelor versus clopidogrel in compared with standard DAPT, but no plan for a phase 3 investiga- patients with acute coronary syndromes. N Engl J Med. 2009;361: tion has been communicated so far. 1045-57. DAPT has been the mainstay of ACS pharmacological strate- 5. Tricoci P, Huang Z, Held C, Moliterno DJ, Armstrong PW, gies for decades1. This practice stems from the paradigm that arte- Van de Werf F, White HD, Aylward PE, Wallentin L, Chen E, rial thrombosis is a platelet-mediated process, which is essentially Lokhnygina Y, Pei J, Leonardi S, Rorick TL, Kilian AM, true in the acute phase of ACS but could be different when tran- Jennings LH, Ambrosio G, Bode C, Cequier A, Cornel JH, sitioning to the longer period. Should we broaden our view on Diaz R, Erkan A, Huber K, Hudson MP, Jiang L, Jukema JW, different paradigms? While rivaroxaban struggles to find its clini- Lewis BS, Lincoff AM, Montalescot G, Nicolau JC, Ogawa H, cal way in ACS, current understanding that blocking the thrombin Pfisterer M, Prieto JC, Ruzyllo W, Sinnaeve PR, Storey RF, pathway on top of inhibiting platelets may translate into the sur- Valgimigli M, Whellan DJ, Widimsky P, Strony J, Harrington RA, vival advantage displayed by ATLAS-ACS 2 is worthy of more Mahaffey KW; TRACER Investigators. Thrombin-receptor

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